Glucagon is a 29 amino acid hormone produced by the alpha cells of pancreatic islets. Glucagon is responsible for the maintenance of normal levels of glucose in many animals, including humans, by acting as an insulin-counteracting hormone. In particular, while insulin is known to rapidly decrease blood glucose levels, glucagon counter-balances these effects by contributing to the elevation of blood glucose levels.
The interactions of glucagon and insulin are very important to the maintenance of glucose levels within the body. An imbalance of glucagon or insulin is believed to play a role in several diseases, such as diabetes mellitus and diabetic ketoacidosis. According to one theory, the hyperglycemic state of diabetes mellitus may be brought on not only by glucose under-utilization (due to decreased insulin), but also by the overproduction of glucose due to elevated concentrations of glucagon (see, Unger, "Diabetes and the alpha cell," Diabetes 25:136-151, 1976; Unger and Orci, "The essential role of glucagon in the pathogenesis of diabetes mellitus," Lancet 1:14-16, 1975).
An important factor in the study of glucagon, and glucagon's role in diseases such as diabetes mellitus, is the glucagon receptor, which, upon binding with glucagon, transduces a signal to the cell, thereby triggering glycogenolysis (glycogen hydrolysis), and gluconeogenesis (glucose synthesis).
It is presently believed that glucagon's effects are mediated in part by the elevation of the intracellular levels of cyclic adenosine monophosphate (cAMP). In particular, the binding of glucagon to its cellular receptor activates adenylate cyclase to produce cAMP, thus raising the levels of intracellular cAMP. This elevation of intracellular levels of cAMP is believed to result in glycogenolysis and gluconeogenesis, with the resultant rise in glucose production by the liver (see, Unson et al., "Biological Activities of des-His.sup.1 Glu.sup.9 ! Glucagon Amide, a Glucagon Antagonist," Peptides 10:1171-1177, 1989).
Additional pathways, however, have also been suggested for the stimulation of glycogenolysis and gluconeogenesis. In particular, it has been reported that glucagon binds to receptors in the hepatocyte membrane that are coupled via a G-protein to phospholipase C. Upon stimulation, this protein causes the breakdown of phosphatidylinositol 4,5 biphosphate to produce the second messengers inositol triphospate and 1,2 diacylglycerol (see, Wakelam et al., "Activation of two signal-transduction systems in hepatocytes by glucagon," Nature 323:68-71, 1986; Unson et al., Peptides 10:1171-1177, 1989; and Pittner and Fain, Biochem. J. 277:371-378, 1991). The stimulation by glucagon of inositol phospholipid metabolism may be an additional pathway whereby glucagon can stimulate glycogenolysis and gluconeogenesis.
The present invention discloses glucagon receptor(s), and further provides other related advantages.